Effects of aripiprazole and terguride on dopamine synthesis in the dorsal striatum and medial prefrontal cortex of preweanling rats

Iñiguez, Sergio D.; Cortez, Anthony M.; Crawford, Cynthia A.; McDougall, Sanders A.

doi:10.1007/s00702-007-0820-7

Cited by 9 publications

(9 citation statements)

References 56 publications

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“…The increased concentrations of extracellular DA may facilitate its interaction with D 2 autoreceptors. Previous reports have shown that the dopaminergic tone played a very important role in evidencing the agonist property of ARI ( Iñiguez et al, 2008 ). Similarly, in our present study, we also observed different effects of ARI under different extracellular DA concentrations, which could also represent differences in the dopaminergic tone ( Table 1 ; Figure 3 ).…”

Section: Resultsmentioning

confidence: 97%

“…Nevertheless, a high receptor reserve is necessary but not sufficient for ARI to show its agonist properties: a low dopaminergic tone is also required. Previous papers showing agonist effects of ARI on DA synthesis required a low dopaminergic tone, achieved by reserpine or gamma-butyrolactone treatment to animals ( Kikuchi et al, 1995 ; Iñiguez et al, 2008 ). Reserpine depletes DA stores, and gamma-butyrolactone is considered a nerve impulse inhibitor preventing DA release.…”

Section: Discussionmentioning

confidence: 99%

“…Most of these reports were done in cell lines transfected with a high density of D 2S receptor, which is the main subtype of the D 2 autoreceptors ( Usiello et al, 2000 ). Also, the dopaminergic tone in the surrounding milieu has proved to be very important for evidencing the agonistic profile of ARI ( Iñiguez et al, 2008 ). The functional actions of ARI at cloned human D 2 -DA receptors show a range of actions (agonism, partial agonism, antagonism) depending upon the cell type and function examined ( Lawler et al, 1999 ; Shapiro et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

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Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

Guo

Raivio

Sabriá

et al. 2014

International Journal of Neuropsychopharmacology

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Background:The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D2 receptors, where its degree of efficacy as a partial agonist remains controversial.Methods:We examined the properties of aripiprazole at D2-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2mM K+, low dopaminergic tone) and a stimulated condition (15mM K+, where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions.Results:Aripiprazole under the basal condition acted as an agonist at D2-like autoreceptors and fully activated them at about 10nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D2-like autoreceptor activation. Under the stimulated (15mM K+) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole.Conclusions:Under high dopaminergic tone, aripiprazole acts as a D2-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D2-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D2R ligand.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

Guo

Raivio

Sabriá

et al. 2014

International Journal of Neuropsychopharmacology

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“…Under these conditions, the mGlu 2/3 receptor agonist LY379268 was without effect on striatal or accumbens DOPA accumulation at either 3 or 10 mg/kg. In contrast, the partial D 2 receptor agonists aripiprazole or S-(Ϫ)-3-PPP and the full D 2 agonist quinpirole reduced both striatal and accumbens DOPA accumulation, consistent with their intrinsic activity at the D 2 receptor (Hjorth et al, 1988;Svensson et al, 1991;Iñ iguez et al, 2008). In a second experiment, we assessed the ability of LY379268 or the D 2 /D 3 antagonist haloperidol to block partial D 2 agonistmediated reductions in DOPA accumulation in reserpinized rats.…”

Section: Discussionmentioning

confidence: 95%

In Vitro and in Vivo Evidence for a Lack of Interaction with Dopamine D₂ Receptors by the Metabotropic Glutamate 2/3 Receptor Agonists 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-bicaroxylate Monohydrate (LY354740) and (−)-2-Oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic Acid (LY379268)

Fell

Perry²,

Falcone³

et al. 2009

J Pharmacol Exp Ther

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Some recently published in vitro studies with two metabotropic glutamate 2/3 receptor (mGluR 2/3 ) agonists [(Ϫ)-2-oxa-4-aminobicyclo[3.1.0] hexane-4,6-dicarboxylic acid (LY379268) and 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740)] suggest that these compounds may also directly interact with dopamine (DA) D 2 receptors. The current in vitro and in vivo studies were undertaken to further explore this potential interaction with D 2 receptors. LY379268 and LY354740 failed to inhibit D 2 binding in both native striatal tissue homogenates and cloned receptors at concentrations up to 10 M. LY379268 and LY354740 (up to 10 M) also failed to stimulate [35 S]GTP␥S binding in D 2L -and D 2S -expressing clones in the presence of NaCl or N-methyl-D-glucamine. In an in vivo striatal D 2 receptor occupancy assay, LY379268 (3-30 mg/kg) or LY354740 (1-10 mg/kg) failed to displace raclopride (3 g/kg i.v.), whereas aripiprazole (10 -60 mg/kg) showed up to 90% striatal D 2 receptor occupancy. LY379268 (10 mg/kg) and raclopride (3 mg/kg) blocked d-amphetamine and phencyclidine (PCP)-induced hyperactivity in wild-type mice. However, the effects of LY379268 were lost in mGlu 2/3 receptor knockout mice. In DA D 2 receptor-deficient mice, LY379268 but not raclopride blocked both PCP and d-amphetamine-evoked hyperactivity. In the striatum and nucleus accumbens, LY379268 (3 and 10 mg/kg) was without effect on the DA synthesis rate in reserpinized rats and also failed to prevent S-(Ϫ)-3-(3-hydroxyphenyl)-N-propylpiperidine-induced reductions in DA synthesis rate. Taken together, the current data fail to show evidence of direct DA D 2 receptor interactions of LY379268 and LY354740 in vitro or in vivo. Instead, these results provide further evidence for a novel antipsychotic mechanism of action for mGluR 2/3 agonists.Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system, and the variety of its effects in the brain is regulated in part by the diversity of receptor subtypes that respond to glutamate. These receptors include both ionotropic (ligand-gated ion channels) and metabotropic (G protein-coupled) receptor families (Dingledine et al., 1999;Schoepp, 2001). Although the ionotropic receptors were the first to be discovered and have been of significant interest as potential therapeutic targets, the metabotropic glutamate (mGlu) receptors are now also of great interest for potential pharmacotherapeutic development. There are eight mGlu receptors, which have been divided This work was supported by Eli Lilly and Company, Indianapolis, IN. Article, publication date, and citation information can be found at

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“…Regardless of the model employed, stimulating D 2 autoreceptors with quinpirole inhibited dopamine synthesis in both age groups (Svensson et al, 1991; Andersen et al, 1997; Heidbreder and Baumann 2001; Der-Ghazarian et al, 2010). A different pattern of effects was apparent with D 2 receptor blockade, because haloperidol only increased DOPA accumulation using the “open-loop” model (Carlsson et al, 1976; Svensson et al, 1991, 1993; Iñiguez et al, 2008), but not when haloperidol was co-administered with γ-butyrolactone (Magnusson et al, 1988; Yoshida et al, 2006; but see Iñiguez et al, 2008). Importantly, the present results clearly show that administering Mn on PD 1–21 did not modify the sensitivity of synthesis-modulating autoreceptors in adolescent or adult rats.…”

Section: Discussionmentioning

confidence: 99%

Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats

McDougall

Mohd-Yusof

Kaplan

et al. 2013

European Journal of Pharmacology

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Administering manganese chloride (Mn) to rats on postnatal day (PD) 1–21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as persistent increases in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1–21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., “autoreceptor” doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired.

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Effects of aripiprazole and terguride on dopamine synthesis in the dorsal striatum and medial prefrontal cortex of preweanling rats

Cited by 9 publications

References 56 publications

Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

In Vitro and in Vivo Evidence for a Lack of Interaction with Dopamine D₂ Receptors by the Metabotropic Glutamate 2/3 Receptor Agonists 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-bicaroxylate Monohydrate (LY354740) and (−)-2-Oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic Acid (LY379268)

Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats

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Effects of aripiprazole and terguride on dopamine synthesis in the dorsal striatum and medial prefrontal cortex of preweanling rats

Cited by 9 publications

References 56 publications

Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

In Vitro and in Vivo Evidence for a Lack of Interaction with Dopamine D2 Receptors by the Metabotropic Glutamate 2/3 Receptor Agonists 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-bicaroxylate Monohydrate (LY354740) and (−)-2-Oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic Acid (LY379268)

Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats

Contact Info

Product

Resources

About

In Vitro and in Vivo Evidence for a Lack of Interaction with Dopamine D₂ Receptors by the Metabotropic Glutamate 2/3 Receptor Agonists 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-bicaroxylate Monohydrate (LY354740) and (−)-2-Oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic Acid (LY379268)